In type 1 diabetes (T1DM), left ventricle (LV) dysfunction often precedes or occurs in the absence of coronary artery disease or hypertension. This suggests that diabetes has direct effects on the heart, which can contribute to the development of cardiomyopathy and LV dysfunction through other mechanisms including: microvascular disease, myocardial metabolism and energetic impairment, autonomic neuropathy and oxidative stress. Cardiac autonomic neuropathy (CAN) is associated with an increased prevalence of silent myocardial ischemia, and is an independent predictor of increased cardiac mortality. Sympathetic imbalance associated with CAN may critically influence myocardial glucose utilization and contribute to LV contractile abnormalities and functional deficits. We have previously shown that CAN is associated with diastolic dysfunction in patients with T1DM. Recently, magnetic resonance imaging (MRI) myocardial tagging has been used to demonstrate increased LV torsion in T1DM patients, a measure providing sensitive information on early LV tissue deformation. Our preliminary studies indicated that increased torsion correlates with markers of CAN. Recent evidence also suggests that glycemic variability may influence the risk of cardiovascular complications, possibly through a mechanism mediated by activation of oxidative stress. We have previously found that oxidative stress was highest in CAN subjects, and we hypothesize that this could be secondary to increased glycemic excursions. Based on these data, our hypothesis is that, in T1DM, sympathetic activation induced by acute glycemic fluctuations, in concert with activation of oxidative stress, promotes alterations in myocardial oxidative metabolism and efficiency via catecholamine toxicity. Subsequently, the development of increased LV torsion and strain, diastolic dysfunction, and cardiomyopathy increase the risk of cardiovascular events. We propose to test these hypotheses in a prospective clinical study with two specific aims. Aim 1 will determine the association between sympathetic activation and cardiac metabolic and functional deficits in subjects with T1DM free of coronary artery disease. The manifestations of sympathetic activation will be determined by positron emission tomography (PET) with [11C]meta-hydroxyephedrine ([11C]HED), heart rate variability, and 24-hour blood pressure monitoring in patients with T1DM (5-10 years' diabetes duration). These will be correlated with changes in cardiac oxidative metabolism and efficiency determined by [11C]acetate PET and with LV torsion and strain assessed by cardiac MRI with tagging. Aim 2 will explore the natural history of myocardial dysfunction in T1DM and will identify predictive biomarkers and potential pathways involved in the development of these deficits. Subjects with T1DM recruited in Aim 1 will be followed prospectively for 3 years, while adhering to the current standard of care for T1DM, and re-assessed utilizing the outcome measures described in Aim 1. We will correlate changes in sympathetic function, LV torsion, and efficiency with the magnitude of glycemic excursions and down-stream biomarkers proposed to contribute to the development of small fiber dysfunction and microvascular disease: oxidative stress fingerprints as assessed by gas- chromatography/mass spectrometry, real-time qRT-PCR, poly(ADP-ribose) polymerase activation and deficits of intraepidermal nerve fiber density (IENFD). We will also determine whether these minimally invasive surrogate measures can identify subjects susceptible to the development of sympathetic and cardiac deficits. These studies will help elucidate mechanisms of myocardial dysfunction in T1DM with ultimate goal of designing future studies implementing therapeutic strategies aimed at preventing increased cardiovascular risk in patients with T1DM. PUBLIC HEALTH RELEVANCE: It was shown that the injury to heart nerves in diabetes, called cardiac autonomic neuropathy (CAN), is an independent predictor of cardiovascular disease (CVD) mortality, which is up to 4 fold more in patients with diabetes than the general population. Heart failure contributes to CVD and in type 1 diabetes (T1DM) it may occur in the absence of significant ischemic heart disease. This proposal will test if, in T1DM, wide blood glucose fluctuations lead to diabetic CAN and to impaired heart contractile patterns and will evaluate the natural history of heart failure and enhanced CVD risk in patients with T1DM in the current standard of diabetes care. These studies also seek to characterize minimally invasive and sensitive biomarkers that may predict the development and progression of these deficits in T1DM. Identifying the impact of acute and wide glucose fluctuations in T1DM, and their relationship with CAN and cardiovascular risk, could help clinicians better determine the safe premises for intensifying insulin therapy in this patient population.